The Admissibility of Brain Scans in Criminal Trials: The Case of Positron Emission Tomography

The People of the State of New York v. Herbert Weinstein (1992)1 is one of the earliest and most prominent examples of an attorney offering a Positron Emission Tomography (PET) scan as evidence in a criminal trial. Mr. Weinstein, a 68-year-old, married, Caucasian male worked in advertising. Mr. Weinstein had no past criminal history and no history of violence, but he was accused of strangling his wife and throwing her body from their 12th-story Manhattan apartment to make her death appear to be a suicide. When confronted, Mr. Weinstein admitted his guilt and even readily admitted his attempts to cover up his crime.2 Mr. Weinstein’s lack of emotion when discussing the crime and apparent lack of remorse for his action caused his legal team to question whether the older gentleman could be suffering from a neurological impairment that caused an uncharacteristic act of aggression.3 Acts of aggression have been hypothesized to arise from dysfunction within the prefrontal cortex and impaired connections between the frontal lobe and associated limbic brain regions. Physicians consulting with Mr. Weinstein’s defense attorneys suggested Mr. Weinstein undergo neuropsychological testing and brain scanning that could demonstrate potential structural and/or functional deficits in his brain.

Relative Function: Nuclear Brain Imaging in United States Courts

Neuropsychological testing--medical imaging of the brain structure and function--allows the expert to inform the court on the brain structure and function of the forensic examinee. Supported by extensive clinical use, neuropsychological testing and structural imaging in the form of computerized tomography and structural magnetic resonance imaging have achieved general acceptance in court. However, functional imaging such as functional MRI and nuclear medicine techniques, such as positron emission tomography (PET), have faced more admissibility challenges. While functional imaging is becoming an increasingly important tool in assessing neuropsychiatric illness, we surmise that evidentiary challenges are largely related to the phase of trial in which the nuclear study is offered as evidence. This article will review the basic science of functional nuclear imaging including PET and single photon emission computed tomography. We will then review cases where admissibility of these techniques has been challenged and consider whether and how nuclear brain imaging can influence the outcome of the trial

Multi-Omics Analysis of Multiple Glucose-Sensing Receptor Systems in Yeast

The yeast Saccharomyces cerevisiae has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here, we compare the two glucose receptor systems in S. cerevisiae. The first is a heterodimer of transporter-like proteins (transceptors), while the second is a seven-transmembrane receptor coupled to a large G protein (Gpa2) that acts in coordination with two small G proteins (Ras1 and Ras2). Through comprehensive measurements of glucose-dependent transcription and metabolism, we demonstrate that the two receptor systems have distinct roles in glucose signaling: the G-protein-coupled receptor directs carbohydrate and energy metabolism, while the transceptors regulate ancillary processes such as ribosome, amino acids, cofactor and vitamin metabolism. The large G-protein transmits the signal from its cognate receptor, while the small G-protein Ras2 (but not Ras1) integrates responses from both receptor pathways. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast

Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease.

OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer

ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation

The Admissibility of Brain Scans in Criminal Trials: The Case of Positron Emission Tomography

The People of the State of New York v. Herbert Weinstein (1992)1 is one of the earliest and most prominent examples of an attorney offering a Positron Emission Tomography (PET) scan as evidence in a criminal trial. Mr. Weinstein, a 68-year-old, married, Caucasian male worked in advertising. Mr. Weinstein had no past criminal history and no history of violence, but he was accused of strangling his wife and throwing her body from their 12th-story Manhattan apartment to make her death appear to be a suicide. When confronted, Mr. Weinstein admitted his guilt and even readily admitted his attempts to cover up his crime.2 Mr. Weinstein’s lack of emotion when discussing the crime and apparent lack of remorse for his action caused his legal team to question whether the older gentleman could be suffering from a neurological impairment that caused an uncharacteristic act of aggression.3 Acts of aggression have been hypothesized to arise from dysfunction within the prefrontal cortex and impaired connections between the frontal lobe and associated limbic brain regions. Physicians consulting with Mr. Weinstein’s defense attorneys suggested Mr. Weinstein undergo neuropsychological testing and brain scanning that could demonstrate potential structural and/or functional deficits in his brain.

Multi-Omics Analysis of Multiple Glucose-Sensing Receptor Systems in Yeast

The yeast Saccharomyces cerevisiae has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here, we compare the two glucose receptor systems in S. cerevisiae. The first is a heterodimer of transporter-like proteins (transceptors), while the second is a seven-transmembrane receptor coupled to a large G protein (Gpa2) that acts in coordination with two small G proteins (Ras1 and Ras2). Through comprehensive measurements of glucose-dependent transcription and metabolism, we demonstrate that the two receptor systems have distinct roles in glucose signaling: the G-protein-coupled receptor directs carbohydrate and energy metabolism, while the transceptors regulate ancillary processes such as ribosome, amino acids, cofactor and vitamin metabolism. The large G-protein transmits the signal from its cognate receptor, while the small G-protein Ras2 (but not Ras1) integrates responses from both receptor pathways. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast

A Phase III study of radiation therapy (RT) and O6-benzylguanine + BCNU versus RT and BCNU alone and methylation status in newly diagnosed glioblastoma and gliosarcoma: Southwest Oncology Group (SWOG) study S0001

AIMS: To determine the efficacy of MGMT depletion plus BCNU (carmustine) therapy and the impact of methylation status in adults with glioblastoma (GBM) and gliosarcoma. METHODS: Methylation analysis was performed on GBM patients with adequate tissue samples. Patients with newly-diagnosed GBM or gliosarcoma were eligible for this Phase III open-label clinical trial. At registration patients were randomized to Arm 1: O(6)-BG + BCNU (reduced dose) plus radiation therapy (RT) or Arm 2: BCNU plus radiation therapy. RESULTS: One hundred eighty-three patients with newly diagnosed GBM or gliosarcoma were enrolled from 42 United States institutions; 90 eligible patients received O(6)-BG + BCNU plus radiation therapy (RT), and 89 received BCNU plus RT. The trial was halted at first interim analysis per stopping guidelines due to futility (less than 40% improvement on O6BG + BCNU arm). Following adjustment for stratification factors, there was no significant difference in overall (OS) or progression-free survival (PFS) between the two groups (one sided p=0.94 and p=0.88 respectively). Median OS was 11 months (95% c.i. 8 – 13 months) for patients on the O6BG+BCNU arm and 10 months (95% c.i. 8 – 12) for the BCNU arm. PFS was 4 months for patients in each arm. Adverse events were reported in both arms, with significantly more grade 4 and 5 events in the experimental arm. CONCLUSIONS: The addition of O(6)-BG to the standard regimen of radiation and BCNU for treatment of newly-diagnosed glioblastoma and gliosarcoma did not offer added benefit and in fact caused additional toxicity

Flowering date of taxonomic families predicts phenological sensitivity to temperature: Implications for forecasting the effects of climate change on unstudied taxa.

PREMISE OF THE STUDY: Numerous long-term studies in seasonal habitats have tracked interannual variation in first flowering date (FFD) in relation to climate, documenting the effect of warming on the FFD of many species. Despite these efforts, long-term phenological observations are still lacking for many species. If we could forecast responses based on taxonomic affinity, however, then we could leverage existing data to predict the climate-related phenological shifts of many taxa not yet studied. METHODS: We examined phenological time series of 1226 species occurrences (1031 unique species in 119 families) across seven sites in North America and England to determine whether family membership (or family mean FFD) predicts the sensitivity of FFD to standardized interannual changes in temperature and precipitation during seasonal periods before flowering and whether families differ significantly in the direction of their phenological shifts. KEY RESULTS: Patterns observed among species within and across sites are mirrored among family means across sites; early-flowering families advance their FFD in response to warming more than late-flowering families. By contrast, we found no consistent relationships among taxa between mean FFD and sensitivity to precipitation as measured here. CONCLUSIONS: Family membership can be used to identify taxa of high and low sensitivity to temperature within the seasonal, temperate zone plant communities analyzed here. The high sensitivity of early-flowering families (and the absence of early-flowering families not sensitive to temperature) may reflect plasticity in flowering time, which may be adaptive in environments where early-season conditions are highly variable among years